Obesity is a huge and increasing medical problem, with inadequate therapeutic options. One approach to the treatment of obesity is long-term pharmacotherapy. While only one modestly effective drug marketed in the United States (orlistat), two drugs have recently been approved by the FDA (lorcaserin, Qsymia). The limited efficacy of single agents has lead to the idea that combination therapy will be required. To facilitate combinations, we are testing the physiology of dinitrophenol (DNP) as a model system for chemical uncoupling as a treatment of obesity. We are currently designing animal protocols that will use mice to explore combination therapy for obesity. A specific interest is the rational combination of a centrally (brain) acting drug with one that acts peripherally (outside of the brain). This approach has potential to allow use of lower doses of drugs with complementary mechanisms of action, minimizing adverse effects while maintaining weight reduction efficacy, via targeting of both metabolic rate and food intake. We are also exploring the use of mice housed under thermoneutral conditions to see if this provides a metric of efficacy translatable into humans.